ABSTRACT/DESCRIPTION The major objective of the current project is to understand the reward-related actions of cotinine (COT), the major metabolite of nicotine (NIC), and its potential role in the development of NIC use disorder. The long- term goal is to provide a better understanding of COT-related mechanisms in NIC reinforcement and provide rationale for research targeting the actions of COT for future development of new therapies for aiding smoking cessation. The overarching hypothesis is that COT plays an important role in the development of NIC abuse and addiction through a combination of mechanisms, including its own reinforcing and craving-/relapse- like effects, unique mechanisms involved in these effects, its interactions with NIC to promote reinforcing and craving-/relapse-like effects. A multidisciplinary approach encompassing behavioral neuroscience and neurochemistry will be employed in this project. Thus, Aim 1 will determine the reward-related behavioral and neurochemical effects of COT as compared to NIC. Aim2 will determine potential similarities or differences in mechanisms involved in the reinforcing effects of COT vs NIC. Aim 3 will examine potential interactions between COT and NIC in promote reinforcement. And Aim 4 will investigate the craving-/relapse-like properties of COT and its interactions with NIC to promote craving-/relapse-like effects using reinstatement models. Potential sex differences in COT's actions will also be examined. This is a highly novel project. Information attained will not only significantly increase our understanding of COT-related mechanisms underlying NIC reinforcement and the development of NIC use disorders, but also highlight the importance of targeting COT as a new strategy for treating NIC use disorders.